Interstitial lung diseases (ILDs) are characterized by scarring of the lung that leads to lung dysfunction, which can eventually lead to respiratory failure. There are many ILDs with no known cause, which are termed idiopathic. Idiopathic Pulmonary Fibrosis (IPF) is the most common type of ILD. IPF affects about 170,000 people in Europe and 130,000 people in the United States, with approximately 48,000 new cases diagnosed each year in the US alone and 40,000 people dying in the US annually. IPF mortality rates are very high with median survival of 3-5 years from diagnosis and reported 5-year survival rates of less than 30%, on a par with the most lethal cancers. Until recently few treatment options other than lung transplantation have been shown to be effective and treatment for most patients has been symptom control and palliative care.
IPF is a chronic and fatal disease primarily characterised by a progressive decline in lung function caused by the scarring of lung tissue which results in worsening dyspnea. Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet derived growth factor (PDGF) are known potent mitogens for fibroblast cells, which then replace the normal tissue in lungs when fibrosis occurs. In ILDs, the evidence for a pathogenic role for PDGF, VEGF, and FGF has been demonstrated clinically. The primary site affected is the interstitium, the tissue between the air sacs in the lung, but it does also affect the airspaces, peripheral airways and vessels. The disease process is believed to be initiated by a series of microinjuries to the alveolar epithelium in the lung. After the injury, increased vascular permeability leads to clot formation and resident epithelial cells proliferate in an attempt to replace those cells that died as a result of the injury. This process triggers the release of a variety of growth factors (eg, PDGF, VEGF, FGF, and transforming growth factor β (TGFβ), leading to the aberrant activation of the epithelial cells, abnormal vascular remodelling, and most notably, the proliferation and migration of fibroblasts into the lung. Growth factors also induce resident cells to transform into myofibroblasts, which together with fibroblasts organize into foci (King T E Jr, et al., Lancet, 2011, 3; 378(9807):1949-61; Selman M, et al., Ann Intern Med., 2001, 16; 134(2):136-51). These cellular changes result in the disruption of the basement membrane and excessive accumulation of extracellular matrix proteins in the interstitial space. The result is the eventual destruction of the normal architecture of the alveolar capillary unit and lung scarring. The pathologies that define the usual interstitial pattern (UIP) of fibrosis characteristic of IPF are a heterogeneous pattern of alternating areas of normal lung, interstitial inflammation, dense fibrosis, fibroblastic foci, and honeycombing, especially in the subpleural area of the lung (Du Bois R M., Nat Rev Drug Discov., 2010, 9(2):129-40; Selman M, et al., Ann Intern Med., 2001, 16; 134(2):136-51; King T E Jr, et al., Lancet, 2011, 3; 378(9807):1949-61). The loss of normal architecture and scarring of the interstitial space leads to a significant decline in gas exchange capacity leading to development of the classical symptoms of the disease namely dyspnea, chronic cough, inspiratory crackles on auscultation, and abnormal spirometry (Castriotta R J, et al., Chest, 2010, 138(3):693-703). While the disease course is heterogeneous, the median survival is approximately 3-5 years and the most common cause of death is respiratory failure due to the progressive pathologies that disrupt normal lung functioning and gas-exchange.
To achieve better tolerability and also better efficacy in treatment of lung disorders it can be advantageous to deliver a drug directly to the site of action in the lung. This enables higher concentrations of drug to be achieved at the site of action resulting in a lower overall dose consequently lowering systemic side effects.
Nintedanib, a protein kinase inhibitor, was approved by the FDA for treatment of IPF in 2014 by oral administration. However, it is associated with significant systemic adverse events, including abdominal pain, vomiting and diarrhoea. WO2006/067165 teaches that inhibitors of VEGFR, FGFR and PDGFR, such as nintedanib, may be expected to be useful in treatment of fibrotic diseases, such as IPF. Fehrenbach, H., et al., Virchows Arch., 1999, 435(1):20-31 discloses that VEGFR is linked to the cause of pulmonary fibrosis. Lindroos. P., Am J Physio Lung Cell Mol Physiol., 2001, 280:L354-L362 teaches that the upregulation of PDGF receptor is a mechanism of myofibroblast hyperplasia during pulmonary fibrosis. WO01/27081 shows that compounds that have inhibiting effects on kinases, including VEGFR, PDGFR and FGFR, are suitable for treating fibrotic diseases and discloses a series of 6-position substituted indolinones. Similarly, WO2006/067165 and WO2006/067168 also disclose 6-position substituted indolinones for use as medicaments for the treatment or prevention of fibrotic diseases.
There remains a need in the art to develop further compounds, especially compounds that are better tolerated than nintedanib, for treating fibrotic diseases and interstitial lung diseases, such as IPF. Desirably such compounds would have low dose, long duration of action suitable for once, twice or three times daily dosing and good efficacy and tolerability especially when delivered topically to the lung. The compounds of formula (I) described herein address this issue.